The invention relates to topical cosmetic compositions, in particular, skin lightening compositions, comprising benzaldoximes having at least one aromatic hydroxyl or alkoxy group for cosmetic or dermatological applications.
Skin-lightening active ingredients somehow interfere with melanin metabolism or catabolism. The melanins, which are usually brown to black in color, are formed in the melanocytes of the skin, transferred to the keratinocytes and cause the coloration of skin or hair. The brown-black eumelanins are formed in mammals predominantly from hydroxy-substituted aromatic amino acids such as L-tyrosine and L-DOPA, and the yellow to red pheomelanins are additionally formed from sulfur-containing molecules (Cosmetics and Toiletries 1996, 111 (5), 43-51). Starting from L-tyrosines, the copper-containing key enzyme tyrosinase forms L-3,4-dihydroxyphenylalanine (L-DOPA), which for its part is oxidized again by the tyrosinase via the red-brown dopaquinone to give melanin. A comparison of tyrosinases from plants, fungi and mammals shows that the mechanism and the substrate specificity is comparable in all of the tyrosinases examined.
If, for some reason, the melanin-forming melanocytes are not distributed evenly in the human skin, pigmentation spots form, which are either lighter or darker than the surrounding areas of skin. In order to overcome this problem, skin lightening compositions are offered on the market which help to at least partially even out pigmentation spots. In addition, many people have a desire to lighten their naturally dark skin color. Very safe and effective skin lightening compositions are required for this purpose. Many skin lightening compositions comprise tyrosinase inhibitors of greater or lesser strength.
Commercially available skin lightening compositions comprise, in particular, hydroquinone, hydroquinone derivatives, such as, for example, arbutin, vitamin C, derivatives of ascorbic acid, such as, for example, ascorbyl palmitate, kojic acid and derivatives of kojic acid, such as, for example, kojic acid dipalmitate.
One of the most frequently used skin lighteners is hydroquinone. However, the substance has a cytotoxic effect towards melanocytes and can damage the skin. For this reason, such preparations are no longer authorized for cosmetic applications in, for example, Japan and South Africa. In addition, hydroquinone is very oxidation-sensitive and can only be stabilized, with difficulty, in cosmetic formulations.
Vitamin C and ascorbic acid derivatives have only an inadequate action on the skin. Further, they do not act directly as tyrosinase inhibitors, but reduce the colored intermediates of melanin biosynthesis.
Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) is a tyrosinase inhibitor which, by chelating the copper atoms of the enzyme, inhibits the catalytic activity of the latter; it is used in commercial skin lightening compositions. The substance is formed predominantly in Aspergillus cultures and can only be isolated therefrom in small amounts.
The object of the present invention was to find low-cost, easy-to-prepare, highly effective tyrosinase inhibitors which can be used as active ingredients in skin lightening compositions.
The invention relates to topical cosmetic compositions comprising benzaldoximes of the general formula 
geometric isomers thereof or mixtures of these isomers
wherein
R1, R5 independently of one another are hydrogen atoms or alkyl groups having from 1 to 4 carbon atoms,
R2, R3 and R4 independently of one another are hydrogen atoms, hydroxyl groups, alkyl groups having from 1 to 4 carbon atoms or xe2x80x94Oxe2x80x94R7 groups, where R7 can be an alkyl group having from 1 to 4 carbon atoms or an arylalkyl group having from 7 to 10 carbon atoms,
with the proviso that at least one of the radicals R2 to R4 is a hydroxyl group or an xe2x80x94Oxe2x80x94R7 group, where R7 is as defined above,
and
R6 is a hydrogen atom, an alkyl or alkenyl group having from 1 to 12 carbon atoms or an optionally substituted aryl or arylalkyl group having from 7 to 10 carbon atoms or an optionally substituted heteroaryl or heteroarylalkyl group having from 2 to 10 carbon atoms which contain one or more heteroatoms from the group consisting of sulfur, nitrogen and oxygen.
Preference is given to topical cosmetic compositions comprising benzaldoximes of the general formula 
geometric isomers thereof or mixtures of these isomers, wherein
R1 and R5 are hydrogen,
and
R2, R3 and R4 independently of one another are hydrogen atoms, hydroxyl groups, alkyl groups having from 1 to 4 carbon atoms or xe2x80x94Oxe2x80x94R7 groups, where R7 can be an alkyl group having from 1 to 4 carbon atoms or an arylalkyl group having from 7 to 10 carbon atoms,
with the proviso that at least one of the radicals R2 to R4 is a hydroxyl group or an xe2x80x94Oxe2x80x94R7 group, where R7 is as defined above,
and
R6 is a hydrogen atom, an alkyl or alkenyl group having from 1 to 12 carbon atoms or an optionally substituted arylalkyl group having from 7 to 10 carbon atoms.
Particular preference is given to topical cosmetic compositions comprising benzaldoximes chosen from the group comprising, for example,
4-hydroxybenzaldoxime;
3,4,5-trihydroxybenzaldoxime;
3-hydroxy-4-methoxybenzaldehyde O-ethyloxime;
3-ethoxy-4-hydroxybenzaldehyde O-ethyloxime;
3,4-dihydroxybenzaldoxime;
3-hydroxy-4-methoxybenzaldoxime;
4-hydroxy-3-methoxybenzaldehyde O-ethyloxime;
3,4-dihydroxybenzaldehyde O-(4-methylbenzyl)-oxime;
3-ethoxy-4-hydroxybenzaldoxime;
4-hydroxy-3-methoxybenzaldoxime;
3,4-dihydroxybenzaldehyde O-ethyloxime;
but not limited thereto.
Surprisingly, we have now found that the benzaldoximes present in the topical compositions according to the present invention are particularly effective tyrosinase inhibitors. In particular, many of the benzaldoximes according to the present invention are significantly more effective than kojic acid. They can, therefore, be used as active ingredients in cosmetic or dermatological skin lightening compositions.
The topical cosmetic compositions according to the present invention, in particular, skin lightening compositions comprising the benzaldoximes are prepared by customary methods known per se by incorporating one or more of the benzaldoximes according to the present invention into cosmetic or dermatological formulations which have the customary composition and, in addition to the skin lightening action, can also be used for the treatment, care and cleansing of skin or hair and as make-up products in decorative cosmetics.
Accordingly, the present invention also relates to topical cosmetic compositions, in particular, cosmetic and dermatological skin lightening compositions, which comprise the benzaldoximes, according to the present invention, in an effective amount alongside other, otherwise customary composition constituents. They comprise from 0.01% by weight to 30% by weight, preferably from 0.01 to 20% by weight, but, in particular, from 0.01% by weight to 5% by weight, based on the total weight of the formulation, of the benzaldoximes according to the present invention and can be in the form of xe2x80x9cwater-in-oilxe2x80x9d, xe2x80x9coil-in-waterxe2x80x9d, xe2x80x9cwater-in-oil-in-waterxe2x80x9d or xe2x80x9coil-in-water-in-oilxe2x80x9d emulsions, microemulsions, gels, solutions, e.g., in oils, alcohols or silicone oils, sticks, soaps, aerosols, sprays and also foams. Further customary cosmetic auxiliaries and additives can be present in amounts from 5 to 99% by weight, preferably from 10 to 80% by weight, based on the total weight of the formulation. In addition, the formulations can comprise water in an amount up to 99.99% by weight, preferably from 5 to 80% by weight, based on the total weight of the formulation.
Some of the benzaldoximes present in the skin lightening compositions according to the present invention are known. The known benzaldoximes according to the present invention are described, for example, in Chem. Ber. 1883, 16, 1780 to 1787, Chem. Ber. 1941, 74, 79, 87 and 89, Chem. Ber. 1922, 55, 920 to 929, in Chem. Ber. 1922, 55, 2357 to 2372 and in Liebigs Ann. 1936, 526, 277 to 294. References to an action as tyrosinase inhibitors and their use in cosmetic and/or dermatological preparations are not made. The benzaldoximes according to the present invention present in the skin lightening compositions are, if still unknown, prepared by processes known to the person skilled in the art by reacting the corresponding benzaldehydes with the corresponding hydroxylamines or salts thereof in a solvent, preferably in water, an aliphatic alcohol having from 1 to 4 carbon atoms or a mixture of these solvents, using an auxiliary base, preferably sodium hydroxide or sodium acetate, at 0xc2x0 C. to 120xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C., where appropriate, neutralized with a mineral acid and purified using the customary methods, preferably by crystallization.
The benzaldehydes used are preferably 4-hydroxybenzaldehyde, 3,4,5-trihydroxybenzaldehyde (gallaldehyde), 4-methoxy-3-hydroxy-benzaldehyde (isovanillin), 3-ethoxy-4-hydroxybenzaldehyde (ethylvanillin), 3,4-dihydroxybenzaldehyde (protocatechualdehyde) or 4-hydroxy-3-methoxybenzaldehyde (vanillin).
Preferred hydroxylamines are hydroxylamine, O-ethylhydroxyl-amine or O-4-methylbenzylhydroxylamine or the salts of the said hydroxylamines.
The topical cosmetic compositions according to the present invention, in particular, skin lightening compositions, can comprise cosmetic auxiliaries and additives, as are usually used in such preparations, e.g., sunscreens (e.g., organic or inorganic light filter substances, preferably micropigments), preservatives, bactericides, fungicides, virucides, ingredients which have a cooling action, plant extracts, antiinflammatory active ingredients, substances which accelerate wound healing (e.g., chitin or chitosan and derivatives thereof), film-forming substances (e.g., polyvinylpyrrolidones or chitosan or derivatives thereof), customary antioxidants, vitamins (e.g., vitamin C and derivatives, tocopherols and derivatives, vitamin A and derivatives), 2-hydroxycarboxylic acids (e.g., citric acid, malic acid, L-, D- or dl-lactic acid), skin lighteners (e.g., kojic acid, hydroquinone or arbutine), skin colorants (e.g., walnut extracts or dihydroxyacetone), perfumes, antifoams, dyes, pigments which have a coloring action, thickeners, surface-active substances, emulsifiers, emollients, humectants and/or moisturizers (e.g., glycerol or urea), fats, oils, unsaturated fatty acids or derivatives thereof (e.g., linoleic acid, (xcex1-linolenic acid, xcex3-linolenic acid or arachidic acid and the natural or synthetic esters thereof in each case), waxes or other customary constituents of a cosmetic or dermatological formulation, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents, silicone derivatives or chelating agents (e.g., ethylenediaminetetraacetic acid and derivatives).
The amounts of cosmetic or dermatological auxiliaries and additives and perfume to be used in each case can easily be determined by simple exploratory experiments by the person skilled in the art, depending on the nature of the product in question.
Preferably, the skin lightening compositions according to the present invention comprising the benzaldoximes according to the present invention can also comprise other active ingredients for skin lightening. In particular, the skin lightening compositions according to the present invention can also comprise kojic acid, kojic acid derivatives, ascorbic acid, ascorbic acid derivatives, hydroquinone, hydroquinone derivatives, sulfur-containing molecules, such as, for example, glutathione or cysteine or other synthetic or natural active ingredients for skin lightening, it being possible for the latter to be used also in the form of an extract from plants, such as, for example, bearberry extract and rice extract.
The amount of the abovementioned exemplary other active ingredients for skin lightening (one or more compounds), which are not identical to the benzaldoximes present in the skin lightening compositions according to the present invention, can be, in the skin lightening compositions according to the present invention, from 0.01 to 30% by weight, preferably from 0.01 to 20% by weight, particularly preferably from 0.01 to 5% by weight, based on the total weight of the preparation.
The skin lightening compositions according to the present invention comprising the benzaldoximes according to the present invention can, however, also additionally comprise UVA and/or UVB filter substances, where the total amount of filter substances may be from 0.1 to 30% by weight, preferably from 0.5 to 10% by weight, based on the total weight of the preparations, giving, for example, sunscreens for skin and hair. Examples of UV filter substances which can be used are 3-benzylidenecamphor derivatives (e.g., 3-(4-methylbenzylidene)-dl-camphor), amino-benzoic acid derivatives (e.g., 2-ethylhexyl 4-(N,N-dimethylamino)benzoate or methyl anthranilate), 4-methoxycinnamates (e.g., 2-ethylhexyl p-methoxycinnamate or isoamyl p-methoxycinnamate), benzophenones (e.g., 2-hydroxy-4-methoxybenzophenone), mono- or polysulphonated UV filters [e.g., 2-phenylbenzimidazole-5-sulphonic acid, sulisobenzones or 1,4-bis(benzimidazolyl)-benzene-4,4xe2x80x2,6,6xe2x80x2-tetrasulphonic acid and 3,3xe2x80x2-(1,4-phenylenedimethylidene)-bis-(7,7-dimethyl-2-oxo-bicyclo-[2,2,1]heptane-1-methanesulphonic acid) and salts thereof), salicylates (e.g., 2-ethylhexyl salicylate or homomethyl salicylate), triazines (e.g., 2,4-bis-[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, bis-(2-ethylhexyl) 4,4xe2x80x2-([6-([(1,1 -dimethylethyl)-aminocarbonyl]phenylamino)-1,3,5-triazin-2,4-diyl]dimino)bisbenzoate), 2-cyanopropenoic acid derivatives (e.g., 2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate), dibenzoyl derivatives (e.g., 4-tert.-butyl-4xe2x80x2-methoxydibenzoylmethane), polymer-bonded UV filters (e.g., polymer of N-[2-(or 4)-(2-oxo-3-bomylidene)methyl]-benzylacrylamide) or pigments (e.g., titanium dioxides, zirconium dioxides, iron oxides, silicon dioxides, manganese oxides, aluminium oxides, cerium oxides or zinc oxides).
The lipid phase in the topical cosmetic compositions according to the present invention can advantageously be chosen from the following groups of substances: mineral oils (advantageously paraffin oil), mineral waxes, hydrocarbons (advantageously squalane or squalene), synthetic or semisynthetic triglyceride oils (e.g., triglycerides of capric or caprylic acid), natural oils (e.g., castor oil, olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, borage oil seed oil and the like), natural ester oils (e.g., jojoba oil), synthetic ester oils (preferably esters of saturated and/or unsaturated, linear and/or branched alkanecarboxylic acids carrying from 3 to 30 carbon atoms with saturated and/or unsaturated, linear and/or branched alcohols having from 3 to 30 carbon atoms and esters of aromatic carboxylic acids with saturated and/or unsaturated, linear and/or branched alcohols having from 3 to 30 carbon atoms, in particular, chosen from the group consisting of isopropyl myristate, isopropyl stearate, isopropyl palmitate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl laurate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2-octyldecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate, and synthetic or natural mixtures of such esters), fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty alcohols with alcohols of low carbon number (e.g., with isopropanol, propylene glycol or glycerol) or esters of fatty alcohols with alkanoic acids of low carbon number or with fatty acids, alkyl benzoates (e.g., mixtures of n-dodecyl, n-tridecyl, n-tetradecyl and n-pentadecyl benzoate), and cyclic or linear silicone oils (such as, for example, dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes, and mixed forms thereof).
The aqueous phase of the topical cosmetic compositions according to the present invention optionally, advantageously comprises alcohols, diols or polyols of low carbon number, and ethers thereof, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ethers, propylene glycol monomethyl, monoethyl or monobutyl ethers, diethylene glycol monomethyl or monoethyl ethers and analogous products, and also alcohols of low carbon number, e.g., ethanol, isopropanol, 1,2-propanediol, glycerol, and also xcex1- or xcex2-hydroxy acids, preferably lactic acid, citric acid or salicylic acid, and also emulsifiers, which may be advantageously chosen from the group consisting of ionic, nonionic, polymeric, phosphate-containing and zwitterionic emulsifiers, and, in particular one or more thickeners, which may advantageously be chosen from the group consisting of silicon dioxide, aluminium silicates, such as, for example, bentonites, polysaccharides and derivatives thereof, e.g., hyaluronic acid, guar flour, xanthan gum, hydroxypropylmethylcellulose or allulose derivatives, particularly advantageously from the group of polyacrylates, preferably, a polyacrylate from the group of so-called Carbopols, in each case individually or in combination, or from the group of polyurethanes.
For use, the topical cosmetic compositions according to the present invention, in particular, the skin lightening compositions, comprising the benzaldoximes according to the present invention are applied to the skin and/or hair in a sufficient amount in a manner customary for cosmetics.
The invention is further illustrated but is not intended to be limited by the following examples in which all parts and percentages are by weight unless otherwise specified.